Age-Related Allele-Specific DNA Methylation: Passage of Time or Cell Divisions? Age-related changes in CpG site-specific DNA methylation have been observed in human cohort-based studies as well as longitudinal studies by multiple laboratories, including ours. There is great interest in the possibility that these age-related epigenetic changes are also causally related to aging phenotypes, including common diseases. One of the most interesting questions concerning age-related methylation changes is whether they are caused by passage of time, per se, or related to the number of cell divisions or DNA replications that a particular DNA molecule has undergone. If stem cell divisions/DNA replications are the cause of age-related methylation changes, then an additional hypothesis can be raised concerning the parental origin of age-related methylation changes. In the same way that base substitution mutations occur more frequently in the paternal germline than the maternal germline, if age-related methylation changes occur as a function of the number of stem cell divisions, then age-related methylation changes will accumulate at a greater rate on paternally transmitted alleles than on maternally transmitted alleles. We propose to test the hypothesis that sites at which age-related methylation changes occur accumulate these changes at a greater rate on paternal alleles than on maternal alleles. We will compare methylation levels on paternal and maternal alleles in the oldest and youngest third-generation children from the CEPH Utah genetic mapping families (the average parental age difference between the births of the youngest and oldest same-sex children is 16.1 years). We will examine allele-specific DNA methylation in 96 individuals, total, at ~200 age-related CpG sites that are linked, in cis, to common SNPs. The completion of this study will determine whether parental age contributes significantly to epigenetic variation in the offspring as well as suggest additional mechanisms by which parental age might influence disease risk in offspring.